IHC-P (paraffin)

PD-1 (PDCD1, CD279), TIM-3 (HAVCR2), LAG3 (CD223), VISTA (PD-H1), and B7-H3 (CD276) are immune cell co-inhibitory receptors (also known as immune checkpoints) that negatively regulate T cell function, and dampen the immune response to pathogens and cancer. In addition to activated T cells, PD-1 is expressed by activated B-cells and monocytes. TIM-3 is expressed by exhausted T cells in the settings of chronic infection and cancer. Tumor-infiltrating macrophages and dendritic cells also express TIM-3. LAG3 is primarily expressed by activated CD4+ T cells, CD8+ T cells, FoxP3+ T regulatory cells (Tregs) and natural killer (NK) cells. Although primarily expressed by myeloid cells, VISTA is also expressed by CD4+, CD8+, and Treg cells. Research examining the biological function of B7-H3 suggested that B7-H3 can be both a positive and negative regulator of T cell response. B7-H3 is expressed by antigen presenting cells, activated T cells, and a few normal tissues, including placenta and prostate. Expression of B7-H3 is seen in several cancer types, including prostate, breast, colon, lung, and gastric cancers, and in endothelial cells from tumor associated vasculature. Therapeutic blockade of these immune checkpoint receptors is a promising strategy for neoplastic intervention by enabling anti-tumor immune responses (1-3).

4-1BB (TNFRSF9, CD137), GITR (TNFRSF18), OX40 (TNFRSF4, CD134), and CD40 ligand (CD40L, CD154, TRAP, gp39) are immune cell co-stimulatory receptors that promote effector T cell survival and activation, and enable optimal immune responses to pathogens. 4-1BB is expressed in activated CD4+ and CD8+ T cells, natural killer cells and dendritic cells. GITR is expressed constitutively at high levels on Tregs, at low levels on naive and memory T cells, and is induced upon T cell activation. Studies show GITR can also be induced on NK cells, macrophages, and DCs. GITR ligation has been shown to induce CD8+ T cell activation, cytoxicity, and memory T cell survival, and conversely inhibit Treg suppressive function while promoting effector T cell resistance to Treg suppression. OX40 is primarily expressed on activated CD4+ and CD8+ T cells, while CD40L is primarily expressed on the surface of T cells, but has also been reported in blood platelets, mast cells, basophils, NK cells, and B cells. Research studies show that agonists of these co-stimulatory receptors augment anti-tumor immunity in several cancer types. Due to the combined effects on both Treg suppression and effector cell activation, GITR represents a unique opportunity for immunotherapeutic intervention in cancer. These pathways are an important area of interest in the study of cancer, vascular diseases, and inflammatory disorders (4-7).

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